ER-GUARD: an evolutionarily conserved antioxidant defense system at ER membranes.
Zhijian JiTaruna PandeyHenry de BellyBingying WangOrion David WeinerYao TangShouhong GuangThomas D GoddardDengke K MaPublished in: bioRxiv : the preprint server for biology (2024)
Oxidative protein folding in the endoplasmic reticulum (ER) is essential for all eukaryotic cells yet generates hydrogen peroxide (H2O2), a reactive oxygen species (ROS). The ER-transmembrane protein that provides reducing equivalents to ER and guards the cytosol for antioxidant defense remains unidentified. Here we combine AlphaFold2- based and functional reporter screens in C. elegans to identify a previously uncharacterized and evolutionarily conserved protein ERGU-1 that fulfills these roles. Deleting C. elegans ERGU-1 causes excessive H2O2 and transcriptional gene up- regulation through SKN-1, homolog of mammalian antioxidant master regulator NRF2. ERGU-1 deficiency also impairs organismal reproduction and behaviors. Both C. elegans and human ERGU-1 proteins localize to ER membranes and form network reticulum structures. We name this system ER-GUARD, E ndoplasmic R eticulum Gu ardian A egis of R edox D efense. Human and Drosophila homologs of ERGU-1 can rescue C. elegans mutant phenotypes, demonstrating evolutionarily ancient and conserved functions. Together, our results reveal an ER-membrane-specific protein machinery and defense-net system ER-GUARD for peroxide detoxification and suggest a previously unknown but conserved pathway for antioxidant defense in animal cells.
Keyphrases
- endoplasmic reticulum
- estrogen receptor
- breast cancer cells
- oxidative stress
- transcription factor
- hydrogen peroxide
- reactive oxygen species
- endothelial cells
- induced apoptosis
- protein protein
- genome wide
- anti inflammatory
- nitric oxide
- dna methylation
- copy number
- cell cycle arrest
- high resolution
- cell proliferation
- body mass index
- induced pluripotent stem cells
- innate immune
- crispr cas
- heat shock
- pluripotent stem cells